Relative cytotoxic activity of immunotoxins reactive with different epitopes on the extracellular domain of the c-erbB-2 (HER-2/neu) gene product p185

Boyer, Cinda M.; Pusztai, Lajos; Wiener, Jon R.; Xu, Feng; Dean, Gillian S.; Bast, B. S.; O'Briant, Kathy; Greenwald, Marilee; DeSombre, K.; Bast, Robert C.

doi:10.1002/(sici)1097-0215(19990812)82:4<525::aid-ijc10>3.0.co;2-j

Cited by 21 publications

(13 citation statements)

References 13 publications

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“…Such results are consistent with previous reports of growth inhibition with unconjugated antibodies to HER-2, which showed a maximum growth inhibition of f50% to 67% (39,41). Xu et al (15) reported cytotoxicity levels of up to f80% with the most active of the anti -HER-2 antibodies tested, but they assayed anchorage-independent growth in soft agar, as opposed to growth adherent to plastic, and it is known that the toxic effects of unlabeled antibodies to HER-2 are more pronounced with the soft agar cloning assay (17,41). Cytotoxicity results depend strongly on the particular antibody used (38).…”

Section: Discussionsupporting

confidence: 90%

“…Because of its preferential expression on tumor cells, HER-2 has been tested as a target for antibodies conjugated to a range of radionuclides, drugs, and toxins (16,17,42). Each of these conjugates has certain advantages and disadvantages.…”

Section: Discussionmentioning

confidence: 99%

“…Antibody 21.1 (also called e21; ref. 16) was not included in the major studies of HER-2 epitopes, but we have found that it is efficiently blocked by the antibody 454C11, which was one of the antibodies used by Xu et al (17) and was shown to recognize the NH 2 terminus of the molecule (amino acids 1 -241). These two antibodies, therefore, react with the same, or closely related, epitopes.…”

Section: Introductionmentioning

confidence: 99%

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In vitrocytotoxicity of carcinoma cells with 111In-labeled antibodies to HER-2

Michel

Andrews²,

Castillo³

et al. 2005

Molecular Cancer Therapeutics

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In vitrocytotoxicity of carcinoma cells with 111In-labeled antibodies to HER-2

Michel

Andrews²,

Castillo³

et al. 2005

Molecular Cancer Therapeutics

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show abstract

“…Important factors that contribute to the different signal intensities generated by distinct probes for the same gene include differing GC-nucleotide content, sequence length, intraplatform crossmatch opportunities, and the location of the probe sequence in relation to the 3 ¶-end of the target gene (6). Using a simple analogy, different probes could be considered similar to different antibodies that target distinct epitopes of the same protein (7). The concordance between signal intensities for probes that target the same gene on different platforms is directly related to sequence homology (8,9).…”

Section: Are Dna Microarrays Suitable For Diagnostic Assay Development?mentioning

confidence: 99%

Chips to Bedside: Incorporation of Microarray Data into Clinical Practice

Pusztai

2006

Clinical Cancer Research

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Advances in analytic technologies have often driven progress in medicine. This is particularly true for diagnostics in which new imaging methods and novel molecular analytic tools such as DNA sequencing and PCR have all found their diagnostic niche and are now routinely used in the clinic. Highthroughput microarray-based analytic methods were first described over a decade ago (1). It enabled researchers to simultaneously and semiquantitatively measure the expression of thousands of mRNA species from a biological specimen in a single experiment. Molecular biologists and clinical investigators quickly realized the potential of this technology (2). It was expected that new insights into cell biology would be gained through unbiased analysis of the transcriptome, and that combinations of genes would provide more accurate prognostic and predictive tests than any single gene alone. It may be timely to reflect on what has materialized from these initial hopes, keeping in mind that it often takes several decades for a new technology to mature and show its full effect on science or show its value in clinical medicine.

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“…In addition, because monoclonal antibodies directed at different epitopes of erbB2 show varying levels of internalization (42), other erbB2-targeting sFvs might increase the binding, internalization and ultimately cytotoxicity of bispecific immunotoxin.…”

Section: Discussionmentioning

confidence: 99%

Increasing Anticarcinoma Activity of an Anti-erbB2 Recombinant Immunotoxin by the Addition of an Anti-EpCAM sFv

Stish

Chen

Shu

et al. 2007

Clinical Cancer Research

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Purpose: erbB2, the product of the Her2-neu gene, is a well-established therapeutic target for antibody-based biologicals, but anti-erbB2 antibody-toxin fusion proteins are limited in their activity. The goal of this study was to determine if genetically adding an sFv targeting epithelial cell adhesion molecule (EpCAM) to an anti-Her2 sFv immunotoxin would result in enhanced antitumor activity. Experimental Design: In vitro studies were done in which the new bispecific immunotoxin DTEpCAM23 was compared with monospecific immunotoxins (DTEpCAM and DT23) to quantitate immunotoxin activity. Mixtures of monospecific immunotoxins were tested to determine if they were as effective as the bispecific immunotoxin. Binding and internalization studies were also done. In vivo, bispecific immunotoxins were given i.t. to athymic nude mice bearing HT-29 human colon cancer flank tumors and i.p. to mice with i.p. tumors. Results: DTEpCAM23 bispecific immunotoxins showed far greater activity than monospecific immunotoxin (sometimes over 2,000-fold) against most tumor lines. Bispecific immunotoxin was superior and selective in its activity against different carcinoma cell lines. Bispecific immunotoxin had greater activity than monospecific immunotoxin indicating an advantage of having both sFv on the same single-chain molecule. Binding and internalization studies did not explain the differences between bispecific immunotoxin and monospecific immunotoxin activity. Orientation of the sFvs on the molecule had a significant effect on in vitro and in vivo properties. The bispecific immunotoxins were more effective than the monospecific immunotoxin in the flank tumor mouse model. Conclusions: The synthesis of bispecific immunotoxin created a new biological agent with superior in vitro and in vivo activity (over monospecific immunotoxin), more broad reactivity, more efficacy against tumors in vivo, and diminished toxic effects in mice.

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Relative cytotoxic activity of immunotoxins reactive with different epitopes on the extracellular domain of the c-erbB-2 (HER-2/neu) gene product p185

Cited by 21 publications

References 13 publications

In vitrocytotoxicity of carcinoma cells with 111In-labeled antibodies to HER-2

In vitrocytotoxicity of carcinoma cells with 111In-labeled antibodies to HER-2

Chips to Bedside: Incorporation of Microarray Data into Clinical Practice

Increasing Anticarcinoma Activity of an Anti-erbB2 Recombinant Immunotoxin by the Addition of an Anti-EpCAM sFv

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